The present invention is directed to a process for 3S-(3-pyridylmethyl)-6-(2-quinolyl)methoxy-4S-chromanol, of the formula ##STR1## alternatively named 3S,4S-[(3-pyridyl)methyl]-6-[(2-quinolyl)methoxy]-3,4-dihydro-2H-benzopyra n-4-ol. In this process, the corresponding racemic compound, (+)-cis-(3-pyridylmethyl)-6-(2-quinolyl)methoxy-4-chromanol is resolved using tartaric acid (also known as natural tartaric acid or L-tartaric acid), with isolation of the pure, crystalline, less-soluble, tartrate salt of (I) from ethyl acetate.
The compound (I) is a known inhibitor of 5-lipoxgenase enzyme and antagonist of leukotriene receptors, and is thus useful in the prevention or treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related disease states in mammals, as detailed in published European patent application No. 313295.
The compound (I) was heretofore obtained by resolution of (+)-cis-(3-pyridylmethyl)-6-(2-quinolyl)methoxy-4-chromanol by means of chromatographic separation of derived (R)-(-)-O-acetylmandelate esters. This method involves the discrete chemical steps of esterification and hydrolysis, and in addition, a tedious chromatographic separation step. Thus it has been a desirable goal to find a method for the direct resolution of the corresponding racemate in the form of a preferentially crystallized diastereomeric salt with an optically-active acid, a goal which has been met by the present invention.
Natural L-tartaric acid has been previously used in the resolution of racemic organic amines. However, its use does not assure success in any given instance, since it requires not only that the desired diastereomeric salt, be crystalline, but that it be significantly less soluble than its structurally, very closely related diastereomeric salt, if the desired salt is to be obtained in good yield without tedious fractional crystallization methods. See Wheland, "Advanced Organic Chemistry," 3rd Ed., John Wiley and Sons, Inc., New York, 1960, page 312; and "Left and Right Drugs," Science 84, American Association for the Advancement of Science, Washington, D.C., June, 1984, page 11.
A hydrated L-tartrate salt was previously prepared from acetone by combining already resolved compound of the formula (I) with L-tartaric acid in acetone; EP No. 313295 cited above.